Paclitaxel-lipid prodrug liposomes for improved drug delivery and breast carcinoma therapy

Paclitaxel (PTX) is widely applied for the treatment of unresectable and metastasis breast carcinoma as well as other cancers, whereas its efficacy is always impeded by poor solubility. Liposomes are one kind of the most successful drug carriers which are capable of solubilizing PTX and improving patients’ tolerance owing to excellent biocompatibility and biodegradability. However, poor compatibility between PTX and liposomes compromises the stability, drug loading and anti-tumor capacity of liposomal formulations. To address this issue, three lipids with various chain lengths, namely, myristic acid (MA, 14C), palmitic acid (PA, 16C) and stearic acid (SA, 18C), were conjugated to PTX via ester bonds and the synthesized prodrugs with high lipophilicity were further formulated into liposomes, respectively. All liposomes show high stability and drug loadings, as well as sustained drug release. The chain lengths of lipids are negatively correlated with drug release and enzymatic conversion rates, which further impact the pharmacokinetics, tumor accumulation, and anti-tumor efficacy of liposomal PTX. Neither rapid nor slow drug release facilitates high tumor accumulation as well as anti-tumor efficacy of PTX. Among all liposomes, PTX-PA-loaded liposomes show the longest circulation and highest tumor accumulation of PTX and exert the most potent anti-tumor capacities in vivo, owing to its moderate drug release and enzymatic conversion rate. Witnessing its superior safety, PTX-PA liposomes hold potential for further clinical translation.